Background <p>Multiple sclerosis (MS) is an autoimmune disease affecting the central nervous system. Following the elucidation of the role of B cells in MS pathogenesis, B-cell-depleting agents such as Rituximab have become increasingly utilized. However, the relationship between rituximab therapy and susceptibility to tuberculosis (TB) remains a subject of ongoing investigation, with conflicting evidence in the literature.</p> Case presentation <p>A 55-year-old Iranian woman with multiple sclerosis who had received rituximab for five years presented with high-grade fever, chills, and suprapubic pain. One year before admission, she had developed lower-extremity skin lesions initially diagnosed as eosinophilic fasciitis and later revised to erythema nodosum. Computed tomography revealed a left ovarian mass, a right ovarian cyst, ascites, pulmonary involvement, and bilateral pleural effusions, raising concern for malignancy. Bronchoalveolar lavage polymerase chain reaction confirmed tuberculosis. The patient was treated with the World Health Organization standard anti-TB regimen (isoniazid, rifampin, pyrazinamide, and ethambutol). Rituximab was discontinued; dimethyl fumarate was introduced after four months of therapy and rituximab was reintroduced at six months. At one-year follow-up, there was no TB reactivation and no worsening of MS.</p> Conclusion <p>This case demonstrates an atypical multisystem presentation of tuberculosis in an immunocompromised patient receiving long-term anti-CD20 therapy. Susceptibility was likely multifactorial, including immunosuppression, occupational exposure, MS-related immune dysregulation, and prior corticosteroid use. Clinicians should maintain a high index of suspicion for atypical tuberculosis in immunocompromised patients receiving biologic therapies.</p>